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HGNC Approved Gene Symbol: ALPP
Cytogenetic location: 2q37.1 Genomic coordinates (GRCh38): 2:232,378,751-232,382,889 (from NCBI)
Boyer (1961, 1963) described an electrophoretic variant of alkaline phosphatase (orthophosphoric monoester phosphohydrolase, alkaline optimum; EC 3.1.3.1), which appears in the serum during pregnancy in some women, and demonstrated its origin in the placenta. Since the human placenta is largely fetal in origin, the polymorphism may be a characteristic determined by the fetal genotype. Historically, this was the first described example of a polymorphic placental protein. Robson and Harris (1965) studied the genetics. Beckman et al. (1967) found a rare phenotype, absence of placental alkaline phosphatase, in twins and suggested that these twins might be homozygous for a 'silent allele' ('null allele'). The twins were also concordant for Crouzon craniofacial dysostosis (123500), raising the question of a causal relationship. Palmarino et al. (1979) found evidence for at least 11 different mutant alleles at the placental alkaline phosphatase locus. Garattini et al. (1985) demonstrated 'appreciable amounts' of placental alkaline phosphatase in extracts of liver and intestine. Kam et al. (1985) cloned placental alkaline phosphatase cDNA, sequenced it, and mapped the gene by direct spot-blot hybridization to the DNA of chromosomes resolved by dual laser chromosome sorting. A strong signal was obtained with chromosome 2. With longer exposure, a weaker signal appeared also on chromosome 17. They speculated that PLAP-related gene(s) may be located there. Human testis and thymus contain small amounts of an ALP closely resembling, but not identical to, placental ALP. This ALP has been referred to as placentallike ALP or the Nagao isoenzyme (Henthorn et al., 1987); see 171810. Millan and Stigbrand (1983) maintained that placentallike ALP was probably the product of a separate locus.
Martin et al. (1987) used a cDNA probe in Southern blot analysis of somatic cell hybrid DNA and in situ hybridization to locate PLAP to 2q37. Martin et al. (1987) described a RFLP of the PLAP gene. Griffin et al. (1987) mapped both the placental and the intestinal alkaline phosphatase genes to 2q34-q37 by chromosomal in situ hybridization and hybridization to the DNA of somatic cell hybrids. By in situ hybridization, Raimondi et al. (1988) assigned the ALPP gene to 2q37. Knoll et al. (1988) concluded that 3 closely related alkaline phosphatase genes reside on the long arm of chromosome 2 in man. One of these genes (PLAP; the placental ALP-1, in their symbology) encodes the classic heat-stabile placental alkaline phosphatase; a second (which they referred to as placental ALP-2) is closely related to the first, and may encode the so-called placental ALP-like enzyme of the testis and thymus; the third member of this gene family, the intestinal ALP gene, encodes intestinal alkaline phosphatase (171740). The expression of the intestinal and placental genes is highly tissue-specific in spite of nearly 90% sequence similarity within their exons. Knoll et al. (1988) compared the placental alkaline phosphatase gene with the placentallike gene.
Data on gene frequencies of allelic variants were tabulated by Roychoudhury and Nei (1988).
Henthorn et al. (1986) determined the amino-terminal amino acid sequences of the products of 3 common alleles at the PLAP locus. The sequences differed at position 3, which was found to be proline in the products of ALPP*1 and ALPP*2 (also called types 1 and 2) but leucine in the product of ALPP*3 (also called type 3). From cDNA libraries, clones covering the coding regions of types 1 and 3 cDNAs were isolated. Comparison of the deduced amino acid sequences of type 1 (also called S) and type 3 proteins showed 7 differences out of 513 amino acids, each due to a single base substitution. cDNA sequence comparisons showed 3 silent substitutions in coding regions and 3 base differences in the greater than 1 kb stretch of 3-prime untranslated sequences. Thus, a remarkable degree of allelic variation was found. The differences between type 1 and type 3 were pro3-to-leu, met44-to-val, arg241-to-his, gln255-to-arg, thr263-to-ala, tyr367-to-cys, and ser372-to-gly, respectively.
See 171800.0001 and Henthorn et al. (1986).
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Beckman, L., Beckman, G., Christodoulou, C., Ifekwunigwe, A. Variations in human placental alkaline phosphatase. Acta Genet. Statist. Med. 17: 406-412, 1967. [PubMed: 6072617] [Full Text: https://doi.org/10.1159/000152090]
Beckman, L., Bjorling, G., Christodoulou, C. Pregnancy enzymes and placental polymorphism: alkaline phosphatase. Acta Genet. Statist. Med. 16: 59-73, 1966. [PubMed: 4955840] [Full Text: https://doi.org/10.1159/000151950]
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Boyer, S. H. Human organ alkaline phosphatases: discrimination by several means including starch gel electrophoresis of antienzyme-enzyme supernatant fluids. Ann. N.Y. Acad. Sci. 103: 938-950, 1963. [PubMed: 14014721] [Full Text: https://doi.org/10.1111/j.1749-6632.1963.tb53746.x]
Donald, L. J. The genetics of placental alkaline phosphatase: a possible 'null' allele. Ann. Hum. Genet. 38: 7-18, 1974. [PubMed: 4460867] [Full Text: https://doi.org/10.1111/j.1469-1809.1974.tb01988.x]
Donald, L. J., Robson, E. B. Rare variants of placental alkaline phosphatase. Ann. Hum. Genet. 37: 303-313, 1974. [PubMed: 4812951] [Full Text: https://doi.org/10.1111/j.1469-1809.1974.tb01837.x]
Edwards, J. H., Wingham, J. Data on linkage between the locus determining placental alkaline phosphatase and other markers. Ann. Hum. Genet. 30: 233-237, 1967. [PubMed: 6067799] [Full Text: https://doi.org/10.1111/j.1469-1809.1967.tb00024.x]
Garattini, E., Margolis, J., Heimer, E., Felix, A., Udenfriend, S. Human placental alkaline phosphatase in liver and intestine. Proc. Nat. Acad. Sci. 82: 6080-6084, 1985. [PubMed: 3862120] [Full Text: https://doi.org/10.1073/pnas.82.18.6080]
Gogolin, K. J., Slaughter, C. A., Harris, H. Electrophoresis of enzyme-monoclonal antibody complexes: studies of human placental alkaline phosphatase polymorphism. Proc. Nat. Acad. Sci. 78: 5061-5065, 1981. [PubMed: 6946455] [Full Text: https://doi.org/10.1073/pnas.78.8.5061]
Griffin, C. A., Smith, M., Henthorn, P. S., Harris, H., Weiss, M. J., Raducha, M., Emanuel, B. S. Human placental and intestinal alkaline phosphatase genes map to 2q34-q37. Am. J. Hum. Genet. 41: 1025-1034, 1987. [PubMed: 3687940]
Henthorn, P. S., Knoll, B. J., Raducha, M., Rothblum, K. N., Slaughter, C., Weiss, M., Lafferty, M. A., Fischer, T., Harris, H. Products of two common alleles at the locus for human placental alkaline phosphatase differ by seven amino acids. Proc. Nat. Acad. Sci. 83: 5597-5601, 1986. [PubMed: 3461452] [Full Text: https://doi.org/10.1073/pnas.83.15.5597]
Henthorn, P. S., Raducha, M., Edwards, Y. H., Weiss, M. J., Slaughter, C., Lafferty, M. A., Harris, H. Nucleotide and amino acid sequences of human intestinal alkaline phosphatase: close homology to placental alkaline phosphatase. Proc. Nat. Acad. Sci. 84: 1234-1238, 1987. Note: Erratum: Proc. Nat. Acad. Sci. 84: 4088 only, 1987. [PubMed: 3469665] [Full Text: https://doi.org/10.1073/pnas.84.5.1234]
Kam, W., Clauser, E., Kim, Y. S., Kan, Y. W., Rutter, W. J. Cloning, sequencing, and chromosomal localization of human term placental alkaline phosphatase cDNA. Proc. Nat. Acad. Sci. 82: 8715-8719, 1985. [PubMed: 3001717] [Full Text: https://doi.org/10.1073/pnas.82.24.8715]
Knoll, B. J., Rothblum, K. N., Longley, M. Nucleotide sequence of the human placental alkaline phosphatase gene: evolution of the 5-prime flanking region by deletion/substitution. J. Biol. Chem. 263: 12020-12027, 1988. Note: Erratum: J. Biol. Chem. 264: 2391 only, 1989. [PubMed: 3042787]
Lucarelli, P., Scacchi, R., Corbo, R. M., Benincasa, A., Palmarino, R. Human placental alkaline phosphatase electrophoretic alleles: quantitative studies. Am. J. Hum. Genet. 34: 331-336, 1982. [PubMed: 7072721]
Martin, D., Spurr, N. K., Trowsdale, J. RFLP of the human placental alkaline phosphatase gene (PLAP). Nucleic Acids Res. 15: 9104 only, 1987. [PubMed: 2891112] [Full Text: https://doi.org/10.1093/nar/15.21.9104]
Martin, D., Tucker, D. F., Gorman, P., Sheer, D., Spurr, N. K., Trowsdale, J. The human placental alkaline phosphatase gene and related sequences map to chromosome 2 band q37. Ann. Hum. Genet. 51: 145-152, 1987. [PubMed: 3674755] [Full Text: https://doi.org/10.1111/j.1469-1809.1987.tb01056.x]
Millan, J. L., Beckman, G., Jeppsson, A., Stigbrand, T. Genetic variants of placental alkaline phosphatase as detected by a monoclonal antibody. Hum. Genet. 60: 145-149, 1982. [PubMed: 7076255] [Full Text: https://doi.org/10.1007/BF00569701]
Millan, J. L., Stigbrand, T. Antigenic determinants of human placental and testicular placental-like alkaline phosphatases as mapped by monoclonal antibodies. Europ. J. Biochem. 136: 1-7, 1983. [PubMed: 6193958] [Full Text: https://doi.org/10.1111/j.1432-1033.1983.tb07697.x]
Palmarino, R., Corbo, R. M., Lucarelli, P. Human placental alkaline phosphatase: analysis of genetically determined rare variants. Hum. Biol. 51: 341-352, 1979. [PubMed: 533715]
Raimondi, E., Talarico, D., Moro, L., Rutter, W. J., Della Valle, G., De Carli, L. Regional mapping of the human placental alkaline phosphatase gene (ALPP) to 2q37 by in situ hybridization. Cytogenet. Cell Genet. 47: 98-99, 1988. [PubMed: 3356175] [Full Text: https://doi.org/10.1159/000132518]
Robinson, J. C., Goldsmith, L. A. Genetically determined variants of serum alkaline phosphatase: a review. Vox Sang. 13: 289-307, 1967.
Robson, E. B., Harris, H. Genetics of the alkaline phosphatase polymorphism of the human placenta. Nature 207: 1257-1259, 1965. [PubMed: 5884639] [Full Text: https://doi.org/10.1038/2071257a0]
Roychoudhury, A. K., Nei, M. Human Polymorphic Genes: World Distribution. New York: Oxford Univ. Press (pub.) 1988.
Slaughter, C. A., Gogolin, K. J., Coseo, M. C., Meyer, L. J., Lesko, J., Harris, H. Discrimination of human placental alkaline phosphatase allelic variants by monoclonal antibodies. Am. J. Hum. Genet. 35: 1-20, 1983. [PubMed: 6186142]